LHRH (luteinizing hormone-releasing hormone), also known as GnRH (gonadotropin releasing hormone), is a hypothalamic decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) that regulates the reproductive system of vertebrates. It is released into the capillaries of the hypothalamus-pituitary portal system of the median eminence and the infundibular stalk. By this capillary network, LHRH reaches the anterior pituitary gland and then the gonadal stimulated target cells by the second capillary network. GnRH acts at the membrane level of target cells through receptors with seven transmembrane segments that are coupled to phospholipase C via G proteins to increase intracellular calcium flux. Its action induces the biosynthesis and release of the gonadotropin FSH (follicle-stimulating hormone) and LH (luteinizing hormone). It has been found that LHRH agonists and antagonists are useful for treating female endometriosis, fibroids, polycystic ovarian syndrome, breast cancer, ovarian cancer, endometrial cancer, gonadotropin-induced pituitary desensitization during a medically assisted delivery protocol, male benign prostate enlargement & polymorphism and prostate cancer, and male or female precocious puberty.
Currently used LHRH (Luteinizing hormone-releasing hormone) agonists are peptide compounds that are required to be administered via intravenous or subcutaneous routes due to their low oral bioavailability. In addition, LHRH agonists should be taken for a long period of time as drugs for chronic diseases. It is necessary that drugs of the LHRH group are required to be exposed in their sufficient amount at an initial stage of administration in order to exhibit their therapeutic effects.
One of the LHRH agonists, leuprolide acetate, has a short half-life upon its conventional subcutaneous or intramuscular injection, resulting in a rapid decrease of its blood concentration after administration and its disappearance within a few hours (See J Pharmaceutical Sciences Vol. 73 No. 3, 1984, pp. 298-302). This led to the inconvenience of its daily administration in order to maintain its efficacy, while its inconvenience has been further exacerbated by its administrative mode of injection.
In order to mitigate this drawback, formulations (i.e. sustained release formulations) with their efficacy duration of 4 weeks or longer have been developed and sold. For the purpose of exhibiting its drug efficacy, leuprolide acetate is required to be exposed in a sufficient amount to target sites at the initial stage of its administration. However, the conventional long-lasting (or sustained release) formulations have not met such a requirement due to the low initial release rate of leuprolide acetate. In particular, considering that leuprolide acetate inhibits the levels of circulating sex hormones for 2 to 4 weeks after its initial rise, it is desirable that the initial release rate of leuprolide acetate from its delivery microparticle is high in order for leuprolide to be effective. According to the Food and Drug Administration, it is indicated that high initial release of leuprolide is required to achieve its fast casting effects.
Therefore, in order for leuprolide to exhibit a sufficient pharmacological effect as an LHRH agonist, there is a need for a leuprolide formulation which satisfies both the rapidity of its efficacy at the initial stage of administration and the sustainability of maintaining its certain blood level for an extended period of time after administration.